The shapes of different organs can be explained largely by two fundamental characteristics of their epithelial rudiments--the pattern of branching and the rate of proliferation. Glial cell line-derived neurotrophic factor his recently been implicated in the development of metanephric ureteric epithelium (Pichel, J. G., Shen, L., Sheng, H. Z., Granholm, A. -C., Drago, J., Grinberg, A., Lee, E. J., Huang, S. P., Saarma, M., Hoffer, B. J. Sariola, H. and Westphal, H. (1996). Nature (London) 382, 73-76; Sanchez, M. P., Silo-Santiago, I., Frisen, J., He, B., Lira, S. A. and Barbacid, M. (1996). Nature (London) 382, 70-73; Vega, Q. C., Worby, C. A., Lehner, M. S., Dixon, J. E. and Dressler, G. R (1996). Proc. Natl. Acad. Sci. (USA)93, 10657-10661).
Development of the ureter and urinary collecting duct system of the metanephric kidney is first triggered by a signal from the nephrogenic mesenchyme. This signal induces the nearby Wolffian duct to produce an outgrowth, the ureteric bud, which then elongates, invades the mesenchyme, and undergoes dichotomous divisions. Its tips induce condensation and epithelial conversion of the mesenchyme into excretory tubules (reviewed by Saxen, 1987). Kidney tubule induction and ureteric morphogenesis are regulated reciprocally (Grobstein, 1953; 1955). Attempts to identify the signals involved have traditionally concentrated on the induction of epithelial differentiation of kidney tubules, and some interesting candidate molecules have been identified (Kreidberg et al., 1993; Stark et al., 1994; Dudley et al., 1995, Luo et al., 1995; Perantoni et al. 1995; Torres et al., 1995; Vukieevic et al., 1996). Less is known about the control of ureteric bud growth and differentiation, although some growth factors, such as hepatocyte growth factor/scatter factor (HGF) (Santos et al., 1994; Woolf et al., 1995), transforming growth factor-.beta.1 (TGF.beta.1) (Rilvos et al., 1995), and extracellular matrix molecules (Davis et al., 1995) have been implicated in the regulation of its growth and branching. Moreover, HGF has been shown to regulate branching morphogenesis of kidney-derived Madin-Darby canine kidney (MDCK) epithelial cells in collagen-matrix cultures (Montesano et al., 1991a).
Recent data have shown that glial cell line-derived neurotrophic factor (GDNF) is expressed in the condensing mesenchyme that surrounds the developing ureteric system of kidneys (Hellmich et al., 1996; Suvanto et al., 1996). GDNF is a distant member of the TGF.beta. superfamily (Lin et al., 1993) and maintains dopaminergic, noradrenergic and motor neurones of the central nervous system (Lin et al., 1993; Tomac et al., 1995; Arenas et al., 1995; Henderson et al., 1994; Oppenheim et al., 1995; Yan et al., 1995) as well as various sub-populations of the peripheral sensory and sympathetic neurones (Henderson et al., 1994; Buj-Bello et al., 1995; Ebendal et al., 1995; Trupp et al., 1995).
One known receptor for GDNF is the cRet receptor tyrosine kinase (Takahashi et al., 1988; Trupp et al., 1996; Durbec et al., 1996), which is expressed in several tissues adjacent to sites of GDNF synthesis and it is autophosphorylated upon GDNF binding. The functional receptor complex of GDNF and cRet additionally includes novel type of glycosylphosphatidylinositol-lined (GPI) cell surface receptors, GDNFR-.alpha. (Jing et al., 1996; Treanor et al., 1996) or GDNFR-.beta. (Suvanto et al., 1997; also named TGF-.beta.-related neurotrophic factor receptor, TmR2; Baloh et al., 1997). Comparative analysis of GDNFR-.alpha., GDNFR-.beta. and cRet expression suggests that multiple receptor complexes exist in vivo (Baloh et al. 1997, Suvanto et al. 1997). The ligand specificities of GDNFR-.alpha. and GDNFR-.beta. have not yet been fully resolved, but they bind both GDNF and its novel homologue neurturin (Kotzbauer et al. 1996), and both these GPI-linked receptors can mediate growth factor signaling via cRet (Baloh et al., 1997).
Transgenic mice deficient for GDNF, and those deficient for cRet, show remarkably similar phenotypes that are characterized by a severe defect in intestinal innervation, and renal aplasia or hypodysplasia (Pichel et al., 1996; Schuchardt et al., 1994; 1996). This observation, together with those from antibody inhibition experiments (Vega et al., 1996), suggests strongly that GDNF and cRet play a major role in development of renal epithelia. We disclose herein the target cell types and developmental functions of GDNF in kidney morphogenesis.